17-42317209-A-G

Position:

• chr17-42317209-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_139276.3(STAT3):​c.2117T>C​(p.Leu706Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.44

Genes affected

STAT3 (HGNC:11364): (signal transducer and activator of transcription 3) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]

STAT3 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT3. . Gene score misZ 4.9943 (greater than the threshold 3.09). Trascript score misZ 7.3744 (greater than threshold 3.09). GenCC has associacion of gene with hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 17-42317209-A-G is Pathogenic according to our data. Variant chr17-42317209-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3	c.2117T>C	p.Leu706Pro	missense_variant	22/24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.2117T>C	p.Leu706Pro	missense_variant	22/24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2018

The L706P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L706P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (L706M) and nearby residues (Y705N/C, T708S/N, I711M) have been reported in the Human Gene Mutation Database in association with Hyper-IgE syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2019

For these reasons, this variant has been classified as Pathogenic. The observation of one or more missense substitutions at this codon (p.Leu706Pro and p.Leu706Met) in affected individuals suggests that this may be a clinically significant residue (PMID: 20048285, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual with symptoms consistent with hyper IgE syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 429592). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 706 of the STAT3 protein (p.Leu706Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;T;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L;L;.;L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D;.;D;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.99	D;.;.;D;D
Vest4		0.94
MutPred		0.73		Gain of disorder (P = 0.0052);Gain of disorder (P = 0.0052);.;Gain of disorder (P = 0.0052);.;
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1131691476; hg19: chr17-40469227;